This invention relates to a method of administering AMPA receptor antagonists to treat dyskinesias in mammals, such as humans, resulting from the use of dopamine agonist therapy. Dopamine agonist therapy, as referred to in the present invention, is generally used in the treatment of a central nervous system disorder such as Parkinson's disease. In particular, this invention relates to the treatment of such dyskinesias using one or more AMPA receptor antagonists that are disclosed and claimed in PCT international application number PCT/IB97/00134 (filed Feb. 17, 1997), United States provisional patent application number 60/038905 (filed Feb. 28, 1997), United States provisional patent application number 60/049082 (filed Jun. 9, 1997), United States provisional patent application number 60/049083 (filed Jun. 9, 1997), United States provisional patent application number 60/038540 (filed Feb. 28, 1997), United States provisional patent application entitled "Quinazolin-4-one AMPA Antagonists" filed Jul. 21, 1997 with Bertrand L. Chenard, Willard M. Welch, and Anthony R. Reinhold named as inventors, and United States provisional patent application entitled "Novel Atropisomers Of 2,3-Disubstituted-(5,6)-Heteroarylfused-Pyrimidin-4-ones" filed Aug. 27, 1997 with Bertrand L. Chenard and Willard M. Welch named as inventors. The foregoing United States provisional and PCT international patent applications are incorporated herein by reference in their entirety.
Dyskinesias are involuntary physical movements which may include chorea, tremor, ballism, dystonia, athetosis, myoclonus and tic. Dyskinesias often result from treatment of the physical symptoms of Parkinson's disease. Parkinson's disease is characterized by tremor, rigidity, bradykinesia and postural instability. Such motor abnormalities may be reduced by therapies which increase dopamine receptor stimulation. These therapies include drugs which directly stimulate dopamine receptors (such as bromocriptine) or increase the levels of dopamine (such as L-dopa or drugs which inhibit dopamine metabolism). In the present invention, such therapies which increase dopamine receptor stimulation are referred to generally as dopamine agonist therapy. After a period of chronic administration of dopamine agonist therapy to treat Parkinson's disease, new motor abnormalities may emerge. The motor abnormalities associated with dopamine agonist therapy include choreatic dyskinesias and dystonias. The present invention relates to the treatment of dyskinesias associated with dopamine agonist therapy in the treatment of a central nervous system (CNS) disorder, in particular Parkinson's disease, through the administration of an AMPA receptor antagonist as provided below.
The compounds that may be used in accord with the present invention are antagonists of the AMPA subtype of the glutamate receptor. Glutamate is the principal excitatory neurotransmitter in the central nervous system of mammals. Glutamate synaptic transmission is mediated by several families of receptors including the .alpha.-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), N-methyl-D-aspartate (NMDA), kainic acid (KA), and metabotropic receptors. The AMPA receptor subtype mediates fast excitatory transmission throughout the brain, including areas involved in movement. By inhibiting the AMPA receptor through administration of an AMPA receptor antagonist, dyskinesias associated with dopamine agonist therapy may be treated in accord with the present invention as described below.
AMPA receptor antagonists are referred to in several published patents including the following issued patents (listed by patent number followed by issue date in parentheses): U.S. Pat. Nos. 5,654,303 (Aug. 5, 1997); 5,639,751 (Jun. 17, 1997); 5,614,532 (Mar. 25, 1997); 5,614,508 (Mar. 25, 1997); 5,606,062 (Feb. 25, 1997); 5,580,877 (Dec. 3, 1996); 5,559,125 (Sep. 24, 1996); 5,559,106 (Sep. 24, 1996); 5,532,236 (Jul. 2, 1996); 5,527,810 (Jun. 18, 1996); 5,521,174 (May 28, 1996); 5,519,019 (May 21, 1996); 5,514,680 (May 7, 1996); 5,631,373 (May 20, 1997); 5,622,952 (Apr. 22, 1997); 5,620,979 (Apr. 15, 1997); 5,510,338 (Apr. 23, 1996); 5,504,085 (Apr. 2, 1996); 5,475,008 (Dec. 12, 1995); 5,446,051 (Aug. 29, 1995); 5,426,106 (Jun. 20, 1995); 5,420,155 (May 30, 1995); 5,407,935 (Apr. 18, 1995); 5,399,696 (Mar. 21, 1995); 5,395,827 (Mar. 7, 1995); 5,376,748 (Dec. 27, 1994); 5,364,876 (Nov. 15, 1994); 5,356,902 (Oct. 18, 1994); 5,342,946 (Aug. 30, 1994); 5,268,378 (Dec. 7, 1993); and 5,252,584 (Oct. 12, 1993).